1. Field of the Invention
The present invention relates generally to antibodies that bind to the Interleukin-13 receptor al chain (IL-13Rα1) and antagonize IL-13 receptor-mediated signaling by IL-13 and/or IL-4. More particularly, the present invention provides humanized or human antibodies to mammalian and in particular IL-13Rα1. These antibodies have uses in the treatment or prevention of IL-13- and/or IL-4-mediated diseases or conditions. The present invention further contemplates a method of modulating IL-13- and/or IL-4-mediated diseases or conditions by the administration of the subject antibodies. The present invention further provides an assay system useful for identifying antibodies or other agents which modulate IL-13 and/or IL-4 signaling through an IL-13 receptor complex. Accordingly, a method of screening for modulators of IL-13Rα1/ligand interaction is also provided.
2. Description of the Prior Art
Bibliographic details of the publications referred to in this specification are also collected at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Interleukin-13 (IL-13) is a member of the interleukin (IL) family whose biological effects have significant physiological implications since both up- and down-regulation of activity of this cytokine in vivo could potentially provide pharmacological treatments for a wide range of common pathologies. For this reason, amongst others, the study of IL-13 and other IL molecules is of great medical importance. For example, IL-13 is strongly involved in the induction of IgE and IgG4 production as well as the differentiation of T-helper (Th) cells into a secretory (Th2) phenotype. These immunostimulatory steps are critical in the development of atopic diseases which are a major threat to human health, such as anaphylaxis (Howard et al., Am J Hum Genet. 70(1): 230-236, 2002; Noguchi et al., Hum Immunol 62(11): 1251-1257, 2001) as well as milder conditions such as hay fever, allergic rhinitis and chronic sinusitis which, although not life-threatening, are responsible for considerable morbidity worldwide.
IL-13 is a mediator in the pathology of the acute and chronic stages of asthma. During an asthma attack, its activity increases and its effects include reduction of the capacity of lung epithelial cells to maintain a tight barrier against inhaled particles and pathogens (Ahdieh et al., Am J. Physiol. Cell Physiol. 281(6): C2029-2038, 2000) and promotion of allergen-induced airway hyper-responsiveness (Morse et al., Am. J. Physiol. Lung Cell Mol. Physiol. 282(1): L44-49, 2002). In the longer term, IL-13 promotes non-inflammatory structural changes to asthmatic airways, such as enhanced expression of mucin genes, airway damage and obstruction of the small airways (Howard et al., Am. J. Hum. Genet. 70(1): 230-236, 2002; Danahay et al., Am. J. Physiol. Lung Cell Mol. Physiol. 282(2): L226-236, 2002).
Up-regulation of IL-13 activity may be beneficial in certain immune deficiency conditions to reduce disease progression. In HIV infection, for example, a reduction in secretion by Th2 cells reduces antigen-specific immune responses (Bailer et al., J. Immunol. 162(12): 7534-7542, 1999). IL-13, whose levels gradually decline in accordance with disease progression in HIV, has been found to enhance antigen presentation in immune deficiency conditions and to reduce de novo HIV-infection of macrophages (Bailer et al., Eur. J. Immunol. 30(5): 1340-1349, 2000).
The biological effects of IL-13 are mediated by a dimeric receptor complex comprising the subunits IL-13Rα1 (or the NR4 subunit) and IL-4Rα. It is postulated that IL-13 binding to IL-13Rα1 triggers dimerization with IL-4Rα and activation of intracellular mediators that include the Janus Kinases JAK1 and JAK2, as well as STAT6, ERK and p38 (David et al., Oncogene 20(46): 6660-6668, 2001; Perez et al., J. Immunol. 168(3): 1428-1434, 2002).
IL-13 shows many overlapping biological effects with those of IL-4. IL-13 and IL-4 are related by sequence and are involved in many related processes, such as myelopoiesis and the regulation of monocyte/macrophage pro-inflammatory functions. For example, both IL-13 and IL-4 have been shown to effect B cells in a similar fashion, up-regulating surface molecules such as MHC class II and CD23 molecules, and promoting the secretion of IgG4 and IgE.
The overlapping activities of IL-13 and IL-4 can be explained in part by their shared dimeric receptor complex. The Type I IL-13 receptor complex is comprised of an IL-13Rα1 and an IL-4Rα; this same receptor complex is also the Type II IL-4 receptor complex (Callard et al., Immunology Today 17(3): 108, 1996). As such, in looking to achieve therapeutic control of the IL-13 receptor complex by blocking cytokine mediated signaling, it may be useful to have not only a molecule that antagonized signaling mediated by IL-13, but a molecule that antagonized signaling mediated by both IL-13 and IL-4.
Antibodies to IL-13Rα1 may potentially act as antagonists of IL-13-signaling through IL-13 receptor complex. International Patent Publication No. WO 97/15663 suggests antibodies to human IL-13Rα1 as potential therapeutic agents. Gauchat et al. (Eur. J. Immunol. 28: 4286-4298, 1998) reported murine antibodies to human IL-13Rα1 which blocked interaction of a tagged IL-13 with a tagged and immobilized soluble IL-13Rα1. The antibodies also inhibited IL-13 binding to IL-13Rα1 in transfected HEK-293 cells. However, all of these antibodies failed to neutralize IL-13 induced biological activity, suggesting that they were not antagonists of the complete IL-13Rα1/IL-4Rα receptor complex. In a later paper, Gauchat et al. (Eur. J. Immunol. 30: 3157-3164, 2000) reported a rat antibody, designated as C41, to murine IL-13Rα1 which bound to HEK-293 cells transfected with murine IL-13Rα1. However, C41 did not neutralize IL-13 induced biological activities. Further, C41 did not react with the soluble form of human IL-13Rα1. Akaiwa et al. (Cytokine 13: 75-84, 2001) reported an antibody that recognized soluble IL-13Rα1 by enzyme immunoassay and a tagged full length IL-13Rα1 transfected into COST cells. The antibody was used for immunohistochemistry but there is no indication as to whether it was a neutralizing antibody.
In accordance with the present invention, antibodies are generated which bind to the IL-13Rα1 chain, block IL-13 binding to the IL-13Rα1 chain and which antagonize IL-13 signaling through the IL-13Rα1/IL-4Rα complex. Such antibodies are proposed to inhibit IL-13 mediated biological activity. In a preferred embodiment, some antibodies of the present invention surprisingly antagonize signaling by both IL-13 and IL-4 through the IL-13Rα1/IL-4Rα complex.